Tablets containing anion exchange resin

ABSTRACT

The present invention relates to a pharmaceutical composition comprising anion exchange resin, silicon dioxide, crystalline cellulose, and pharmaceutically acceptable carriers and more particularly to tablets containing anion exchange resin prepared by mixing anion exchange resin, silicon dioxide and crystalline cellulose without adding water and tabletting the mixture. More preferably, the present invention relates to said pharmaceutical composition or tablets wherein the anion exchange resin is non-crosslinked anion exchange resin represented by the formula (I): ##STR1## wherein R 1  is an aralkyl group having from 7 to 10 carbon atoms or An alkyl group having from 1-20 carbon atoms; R 2  and R 3  are each independently the same or different and represent a lower alkyl group having from 1-4 carbon atoms; R 4  is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; X is a physiologically acceptable counter ion; n is an integer of from 1 to 3; and p is an average degree of polymerization of from 10 to 10,000.

This application has been filed under 37CFR371. The InternationalApplication number is PCT/JP96/02189.

TECHNICAL FIELD

The present invention relates to tablets containing anion exchange resinuseful as a cholesterol depressant, particularly non-crosslinked anionexchange resin represented by the formula (I): ##STR2## (wherein R₁ isan aralkyl group having from 7 to 10 carbon atoms or An alkyl grouphaving from 1 to 20 carbon atoms; R₂ and R₃ are each independently thesame or different and represent a lower alkyl group having from 1 to 4carbon atoms; R₄ is a hydrogen atom or a lower alkyl group having 1-4carbon atoms; X is a physiologically acceptable counter ion; n is aninteger of from 1 to 3; and p is an average degree of polymerization offrom 10 to 10,000)

and the invention relates to coating tablets using the same, and moreparticularly, to coating tablets with excellent stability, in which thecontent of the active ingredient is increased in order that they can beadministered with ease and that the number of the tablets to beadministered can be decreased.

In addition, the invention also relates to a method for producing thetablets and coated tablets.

BACKGROUND ART

Cholestyramine of a crosslinked type, which is a conventionalcholesterol depressant, is problematic in that its amount to beadministered is large (8 to 16 g/day) and that it must be administeredin the form of its suspension. Therefore, many studies have heretoforebeen made to produce tablets and coated tablets of anion exchangeresins. For example, a method has been reported of coating tablets of asolid cholestyramine resin having a water content of from 8 to 14% witha melt of polyethylene glycol and stearic acid in the presence of nosolvent to give coated tablets, which do not swell in the mouth (seeJapanese Patent Application Laid-Open No. 3-236326).

Regarding tablets of an imidazole-type anion exchange resin (seeJapanese Patent Application Laid-Open No.60-209523), known are a methodof producing those tablets in the presence of a predetermined amount ofwater (see Japanese Patent Application Laid-Open No. 2-286621); a methodof producing coated tablets by coating those tablets as prepared in thepresence of a predetermined amount of water, with hydroxypropylcellulose or the like (see Japanese Patent Application No. 4-320155(published before examination as Laid-Open No. 6-157325)); and a methodof producing those tablets in the presence of a predetermined amount ofwater and silicon dioxide (see Japanese Patent Application Laid-Open No.7-97330).

However, the conventional methods require the addition of apredetermined amount of water to the hygroscopic anion exchange resinsbeing tabletted.

The present inventors have already reported that non-crosslinked anionexchange resin represented by the formula (I): ##STR3## (wherein R₁ isan aralkyl group having from 7 to 10 carbon atoms or An alkyl grouphaving from 1 to 20 carbon atoms; R₂ and R₃ are each independently thesame or different and represent a lower alkyl group having from 1 to 4carbon atoms; R₄ is a hydrogen atom or a lower alkyl group having 1-4carbon atoms; X is a physiologically acceptable counter ion; n is aninteger of from 1 to 3; and p is an average degree of polymerization offrom 10 to 10,000) is extremely useful as a cholesterol depressant (WO93/13781). Because this anion exchange resin is a non-crosslinked andlinear polymer, it does not expand by swelling unlike cross-linkedpolymers such as cholestyramine and so on, so there is no side effectssuch as feeling of distension in the abdomen or constipationaccompanying swelling. Further, the effective adsorption of bile acidper unit weight is large, so it is anion exchange resin of extremelyhigh usefulness.

However, this agent is soluble in water and has strong astringency, andin addition, it is highly hygroscopic and deliquescent. Therefore, thenovel, non-crosslinked cholesterol depressant comprising the compound offormula (II) is problematic in that, if tabletted in any of theconventional methods that require water in the mixing step, it is formedinto tablets with poor strength and stability since its flowability andtablettability is very poor. Even if the cholesterol depressantcomprising the compound of formula (II) is tabletted in the absence ofwater, the resulting tablets are still problematic in that they are veryastringent because of the strong astringency intrinsic to the compoundof formula (II) itself. The dose of the compound of formula (II), thoughvarying depending on the case to which it is administered, is relativelylarge or is generally from 0.1 to 9 g/day, preferably from 0.1 to 5g/day. Tablets comprising the compound of formula (II) and containing alarge amount of vehicles in order to reduce the bitterness of thecompound are problematic in that the number of the tablets to beadministered at a time shall be large.

In order to produce practical medicine products comprising the compoundof formula (II) with such extremely high usefulness, it is desired toformulate the compound into highly-stable preparations without strongastringent while adding thereto the smallest possible amount of vehiclesas possible.

DISCLOSURE OF THE INVENTION

As a result of further study in view of the above problem, the presentinventors found that anion exchange resin, particularly non-crosslinkedanion exchange resin represented by the formula (I): ##STR4## (whereinR₁ is an aralkyl group having from 7 to 10 carbon atoms or An alkylgroup having from 1-20 carbon atoms; R₂ and R₃ are each independentlythe same or different and represent a lower alkyl group having from 1 to4 carbon atoms; R₄ is a hydrogen atom or a lower alkyl group having 1-4carbon atoms; X is a physiologically acceptable counter ion; n is aninteger of from 1 to 3; and p is an average degree of polymerization offrom 10 to 10,000) can be industrially prepared tablets by tabletting amixture without adding water, which comprises that the cholesteroldepressant contains non-crosslinked anion exchange resin and that atleast silicon dioxide and crystalline cellulose are added into thedepressant, and further these tablets are coated as base tablets with acoating agent containing cellulose and so on to solve the above problem.

The present invention relates to a pharmaceutical composition containinganion exchange resin, silicon dioxide, crystalline cellulose andpharmaceutically acceptable carriers. Further, the present inventionrelates to tablets containing anion exchange resin prepared by adding atleast silicon dioxide and crystalline cellulose to the anion exchangeresin and tabletting the mixture to which water is not added. Further,the present invention relates to a process for producing tabletscontaining anion exchange resin which comprises adding at least silicondioxide and crystalline cellulose to the anion exchange resin andtabletting the mixture without adding water.

More specifically, the present invention relates to tablets containingnon-crosslinked anion exchange resin prepared by adding at least silicondioxide and crystalline cellulose to the compound represented by theformula (I) and tabletting the mixture without adding water. Further,the present invention relates to a process for producing tabletscontaining non-crosslinked anion exchange resin which comprises addingat least silicon dioxide and crystalline cellulose to the compoundrepresented by the formula (I) and tabletting the mixture to which wateris not added.

If one of the components of silicon dioxide and crystalline celluloselacks, tabletting properties are not only worsened, but tabletting yieldis also significantly worsened due to high scattering of tablet weights,cracking on the surfaces of tablets and fracture of the edges thereof(see Comparative Examples 4 and 5). The present inventors unexpectedlyfound that the anion exchange resin which has been considered difficultfor industrially tabletting without adding water, particularly thenon-crosslinked anion exchange resin represented by the formula (I), canprovide industrially producible tablets by adding suitable amounts ofboth silicon dioxide and crystalline cellulose.

There is a known method of producing anion exchange resin tablets havingexcellent stability under humidity by adding water to suppress thehygroscopicity of anion exchange resin and lessening the rate in changeof the diameters of base tablets caused by relative humidity, followedby further coating them with cellulose (Japanese Patent ApplicationLaid-Open Publication Nos. 97330/95 and 157325/94). However, this priorart method is intended for use in coating of base tablets as corescontaining a predetermined amount of water with a reduced change in thediameters of base tablets against humidity.

The base tablets of the present invention are prepared by tablettinganion exchange resin without adding water, particularly thenon-crosslinked anion exchange resin represented by the formula (I),which is difficult for tabletting due to its strong hygroscopicity, andsaid known method of tabletting base tablets containing a predeterminedamount of water was difficult to apply as such to the highly hygroscopicbase tablets of the present invention.

The present inventors found that by coating the highly hygroscopic basetablets with a coating agent containing cellulose, it is possible toprevent not only the astringency of anion exchange resin, particularlythe compound represented by the formula (I), but also the hygroscopicityof the base tablets to which water is not added, therefore, tabletshaving stability in long-term storage are provided.

Accordingly, the present invention also relates to coating tabletscontaining anion exchange resin, which comprises that base tablets arecoated by coating agents containing celluloses and that the base tabletsare provided by tabletting a mixture of the anion exchange resin addedat least silicon dioxide and crystalline cellulose without adding water,and to a method for producing the same.

More specifically, the present invention relates to coating tabletscontaining non-crosslinked anion exchange resin prepared by adding atleast silicon dioxide and crystalline cellulose to the non-crosslinkedanion exchange resin represented by the formula (I): ##STR5## (whereinR₁ is an aralkyl group having from 7 to 10 carbon atoms or An alkylgroup having from 1-20 carbon atoms; R₂ and R₃ are each independentlythe same or different and represent a lower alkyl group having from 1 to4 carbon atoms; R₄ is a hydrogen atom or a lower alkyl group having 1 to4 carbon atoms; X is a physiologically acceptable counter ion; n is aninteger of from 1 to 3; and p is an average degree of polymerization offrom 10 to 10,000) without adding water and tabletting the mixture toprepare tablets, followed by coating them with a coating agentcontaining celluloses and to a process for producing the same.

The preparation of the present invention is characterized in thatmanufacturing of the preparation with trace fillers, i.e. with a highcontent of drug, is made feasible. Further, the products by the presentinvention can be applied sufficiently to successive productions and toindustrial productions.

The anion exchange resin of the present invention is preferablynon-crosslinked anion exchange resin, more preferably the compoundrepresented by the formula (I).

The substituent group R₁ in the compound represented by the formula (I)is an aralkyl group having from 7 to 10 carbon atoms or An alkyl grouphaving from 1 to 20 carbon atoms, and the aryl group of said aralkylgroup may have a substituent group but is preferably not substituted.More specifically, said alkyl group may be a straight chain or branchedchain. Further more specifically, a benzyl group which may have asubstituent group, phenylethyl group, methyl group, ethyl group,n-propyl group, iso-propyl group, hexyl group, dodecyl group, octadecylgroup, eicosyl group and so on, more preferably a benzyl group, methylgroup, hexyl group, dodecyl group, and octadecyl group can be listed asthe examples.

The substituent groups R₂ and R₃ are each independently the same ordifferent and may be a lower alkyl group having from 1-4 carbon atomswhich may be a straight chain or branched chain. More specifically, amethyl group, ethyl group, n-propyl group, iso-propyl group, n-butylgroup, iso-butyl group and so on, more preferably a methyl group can belisted as the examples.

The substituent group R₄ is a hydrogen atom or a lower alkyl grouphaving from 1-4 carbon atoms which may be a straight chain or branchedchain. More specifically₁ a hydrogen atom, methyl group, ethyl group,n-propyl group, iso-propyl group, n-butyl group, iso-butyl group and soon, more preferably a hydrogen atom or methyl group can be listed as theexamples.

The counter ion X is particularly not limited insofar as it is aphysiologically acceptable counter ion, and halogens, inorganic saltssuch as sulfate, carbonate and so on and organic acid salts such asacetate, propionate, malonate, ascorbate, glucuronate, glutamate,sulfonate, phosphate, preferably halogens, sulfate, phosphate, morepreferably halogens such as chlorine ion, bromine ion and fluorine ioncan be listed as the examples.

The compound shown as the formula (I) of the present invention can beproduced by preparing its corresponding monomer, i.e. quaternaryammonium salt, and then polymerizing it in the presence of apolymerization initiator such as radical polymerization agent.

As the examples of the compound shown as the formula (I) of the presentinvention, the following compounds can be listed:

poly(acryloyloxyethyl-N,N,N-trimethylammonium chloride),

poly(methacryloyloxyethyl-N,N,N-trimethylammonium chloride),

poly(acryloyloxyethyl-N,N-dimethyl-N-benzylammonium chloride),

poly(methacryloyloxyethyl-N,N-dimethyl-N-benzylammonium chloride),

poly(acryloyloxyethyl-N,N-dimethyl-N-hexylammonium chloride),

poly(methacryloyloxyethyl-N,N-dimethyl-N-hexylammonium chloride),

poly(acryloyloxyethyl-N,N-dimethyl-N-dodecylammonium chloride),

poly(methacryloyloxyethyl-N,N-dimethyl-N-dodecylammonium chloride),

poly(acryloyloxyethyl-N,N-dimethyl-N-octylammonium chloride), and

poly(methacryloyloxyethyl-N,N-dimethyl-N-octylammonium chloride).

As a particularly preferable compound of said compoundpoly(acryloyloxyethyl-N,N-dimethyl-N-benzylammonium chloride) can belisted.

The content of the anion exchange resin of the present invention,particularly the compound shown as the formula (I), is in the range offrom 50 to 95% by weight, preferably from 70 to 90% by weight, morepreferably from 75 to 90% by weight, relative to the total weight ofbase tablets.

Silicon dioxide and crystalline cellulose used in the present inventionare not particularly limited inasmuch as they are acceptable foruptaking peroral administration, preferably those having been used asperoral pharmaceutical preparations are industrially suitable.

Silicon dioxide is used to impart fluidity in the invention, and forexample, hydrous silicon dioxide (also called white carbon), silicondioxide (also called silica gel or silicic anhydride) and so on,preferably finely divided silicon dioxide and light silicic anhydridewhich are not hydrous, are used. The apparent specific gravity ofsilicon dioxide used is 70 g/l to 20 g/l, preferably 50 g/l to 20 g/l,and light silicic anhydride with lower apparent specific gravity ispreferable. The adding content of silicon dioxide is 0.01 to 5% byweight, preferably 0.1 to 3% by weight, more preferably 0.1 to 1% byweight relative to the total weight of base tablets.

Crystalline cellulose is preferably fine crystalline cellulose, and theaverage particle diameter of crystalline cellulose is 5 to 50 microns,preferably 10 to 50 microns, more preferably 10 to 30 microns. Theadding content of crystalline cellulose is 0.1 to 30% by weight,preferably 1 to 30% by weight, more preferably 10 to 30% by weightrelative to the total weight of base tablets.

Silicon dioxide used in the present invention, particularly lightsilicic anhydride confers improvements on powder fluidity as its contentincreases and as the apparent specific gravity (bulk density) of silicondioxide decreases, whereas tabletting properties (compressibility) seemto decrease. Therefore, if silicon dioxide is added in an amount of 5parts or more relative to the compound of the formula (I), tablettingproperties are lowered and cracks frequently occur in the resultingtablets.

Crystalline cellulose used in the present invention confers improvementson tabletting properties (compressibility) as its content increases andas the average particle size of crystalline cellulose decreases, whereaspowder fluidity appears to be decreased. With respect to finecrystalline cellulose, if its content exceeds 30 parts, the scatteringof the weights of tablets is raised. Because there is no particularadvantage in using crystalline cellulose in a content of 30 parts ormore relative to the compound of the formula (I), it is preferable toadd inexpensive fillers such as lactose if a large amount of additionalfillers are required.

Accordingly, the present invention relates more specifically to tabletscontaining anion exchange resin prepared by tabletting a water-freemixture containing at least anion exchange resin, preferably thenon-crosslinked anion exchange resin represented by the formula (I),light silicic anhydride with a low apparent specific gravity of 70 g/1to 20 g/l, preferably 50 g/1 to 20 g/l, and crystalline cellulose withan average particle diameter of 50 to 10 microns, preferably 30 to 10microns, as well as to a process for producing the same.

More specifically, the present invention relates to tablets prepared bytabletting a water-free mixture containing at least the non-crosslinkedanion exchange resin represented by the formula (I), silicic anhydridewith a low apparent specific gravity of 50 g/l to 20 g/l, preferably 40g/1 to 20 g/l, and crystalline cellulose with an average particlediameter of 50 to 10 microns, preferably 30 to 10 microns wherein thecontent of said anion exchange resin is 50 to 90% by weight, preferably70 to 90% by weight, more preferably 75 to 90% by weight relative to thetotal weight of tablets, as well as to a process for producing the same.

Further, the present invention relates to coating agents containingnon-crosslinked anion exchange resin prepared by further coating saidtablets with a coating agent containing cellulose, and to a process forproducing the same.

Besides said silicon dioxide and crystalline cellulose, ingredientsconventionally used in tabletting can be added in such a range as not tohinder the object of the present invention to the tablets before coatingwhich serve as the base tablets of the present invention. For example,the following can be added as necessary;

fillers such as disaccharides or monosaccharides such as lactose (milksugar), sucrose, glucose, mannitol, sorbitol and so on, starch such aspotato starch, wheat starch, corn starch, rice starch, inorganicsubstances such as calcium phosphate and calcium sulfate, higher fattyacids and metallic salts thereof (e.g. stearic acid, magnesium stearateand so on),

lubricants such as higher alcohol, talk, synthetic aluminum silicate andso on,

disintegrators such as starch, sodium salts or potassium salts ofcarboxymethyl cellulose, methyl cellulose, carboxymethyl starch, sodiumalginate and so on,

binders such as starch, sucrose, gelatin, gum Arabic, methyl cellulose,carboxymethyl cellulose sodium, polyvinyl pyrrolidone, polymethylpyrrolidone and so on.

The tablets before coating, which serve as the base tablets of thepresent invention, can be produced by mixing the respective ingredientsand tabletting the mixture. The order of addition of the respectiveingredients is not particularly limited, but preferably crystallinecellulose and silicon dioxide are mixed, and then the compoundrepresented by the formula (I) is preferably gradually added and mixed,and other components are added and mixed as necessary to the mixture.

The mallet pressure for tabletting is not particularly limited,preferably 2 tons or less.

The celluloses contained in the coating agent used in the coating stepof the present invention is not particularly limited inasmuch as it ispH independent and water-soluble. Specific examples are hydroxypropylcellulose, hydroxypropyl methyl cellulose, methyl cellulose and so on,among which hydroxypropyl methyl cellulose is preferable.

In the present invention, these of celluloses may be used each solely,or, as necessary, a small amount of wax, titanium oxide, talk, lowsubstituted hydroxypropyl cellulose, polyethylene glycol, triethylcitrate and soon can also be added to the celluloses for use. Forstrength and from an economical viewpoint of the resulting coating film,polyethylene glycol (Macrogol) is preferably added.

The amount of cellulose coated is too large if the concentration ofcellulose in the coating solution is high, so its use at highconcentration is not preferable, and its concentration is preferablyless than 20% by weight, more preferably about 6 to 15% by weight. Ifpolyethylene glycol (Macrogol) is to be added, its concentration ispreferably about 1 to 50% by weight, more preferably about 5 to 40% byweight.

As other coating agents, acid-soluble coating agents can be used. Forexample, it is possible to use coating agents dissolving in gastricacid, such as diethyl aminomethacrylate, polyvinyl acetal diethylaminoacetate (AEA), dimethyl aminoethyl methacrylate-methyl methacrylatecopolymer (trade name: Eudragit E (methyl methacrylate-butylmethacrylatedimethyl aminoethyl methacrylate copolymer)), celluloseacetate N,N-di-n-butylhydroxypropyl ether (CABP) and so on.

The method of coating is not particularly limited, but spray coating ispreferable.

Preferably, the amount of the coating is such that the coating filmitself is coated in an amount of 1 to 10% by weight relative to thetablets (base tablets). For the purpose of masking of astringency, itseffect can be achieved in an amount of 1% by weight or more, but thereis no particular usefulness even if 10% by weight or more coating isapplied, and about 3% by weight coating is most preferable. For coating,the water content of base tablets is measured and the step of coating iscontinued until there is no increase in water content.

Hereinafter, the present invention is described in more detail withreference to Examples, but it is evident that the invention is notlimited to the following examples insofar as the scope of the inventionlies in the gist thereof.

EXAMPLE 1

(1) Mixing Step

The following mixing apparatus was used for mixing each ingredient.

Mixing apparatus: POWREX V-type mixing machine FMV100

(1-1) Mixing method

1000 g of crystalline cellulose and 50 g of light silicic anhydrideshown in the mixture formulation below were weighted, introduced intothe mixing machine and mixed for 5 minutes.

The total amount of poly(acryloyloxyethyl-N,N-dimethyl-N-benzylammoniumchloride) (the compound (referred to hereinafter as "Compound 1") of theformula (I) wherein R₁ is a benzyl group, R₂ and R₃ are methyl groups,R₄ is a hydrogen atom, n is 2, and X is a chlorine ion) was divided into4 portions and each portion was added to said mixture at 5-minuteintervals and mixed in it.

Thereafter, 50 g of magnesium stearate was weighed and introduced intothe mixing machine and mixed for 1 minute.

    ______________________________________                                        (1-2) Mixture formulation (10 kg)                                             ______________________________________                                        Compound 1                 8900 g                                             crystalline cellulose (trade name: Abicel PH-F20                                                         1000 g                                             (average particle diameter: 17 microns))                                      magnesium stearate         50 g                                               light silicic anhydride (apparent specific gravity (bulk                                                 50 g                                               density) 30 g/l)                                                              ______________________________________                                    

(2) Tabletting Step

The following tabletting apparatus was used in the tabletting step.

Tabletting apparatus: Rotary type tabletting machine HT-AP15SS (HataTekkosho Co.)

    ______________________________________                                        (2-1) Tabletting conditions                                                   ______________________________________                                        Rotation               35 rpm                                                 Thickness              5 mm                                                   Hardness               7 or more                                              upper and lower mallet pressure                                                                      2 tons or less                                         Forced feeder          used                                                   ______________________________________                                    

(3) Coating Step

The following coating machine was used in the coating step.

Coating machine: Doria coater 650 (POWREX)

(3-1) Coating method

7 kg of the tablets obtained in (2) above are introduced into a pan, andthe coating pan is set at a 0 rpm at a suction air temperature of 80°C., and it is left until its exhaust temperature becomes constant. Atthis time, it is confirmed that the exhaust temperature is 50° C. ormore. 20 tablets are taken and weighed, and then divided into powder,and its water content is determined. The number of revolutions is set at7 rpm, and it is initiated to spray a coating liquid with theformulation shown below at 12 g/min. 30 minutes later, the number ofrevolutions is set at 15 rpm and spraying is conducted at about 18g/min. 20 tablets are sampled and measured for the weight and watercontent of the tablets at suitable intervals. When the water contentdoes not increase any more and the weight of tablets becomes 3% relativeto the base tablets, spraying is terminated and the number ofrevolutions is set at 5 rpm and the tablets are dried for about 60minutes.

    ______________________________________                                        (3-2) Formulation of the coating liquid                                       ______________________________________                                        Hydroxypropyl methyl cellulose 2910                                                                 400 g                                                   Macrogol 6000         120 g                                                   Ion-exchanged water   4600 g                                                  ______________________________________                                    

EXAMPLE 2

(1) Mixing Step

The following mixing apparatus was used for mixing each ingredient.

Mixing apparatus: POWREX V-type mixing machine FMV100

(1-1) Mixing method

2000 g of crystalline cellulose and 50 g of light silicic anhydrideshown in the mixture formulation below are weighted, introduced into themixing machine and mixed for 5 minutes.

The total amount of Compound 1 is divided into 4 portions and eachportion is added to said mixture at 5-minute intervals and mixed in it.

Thereafter, 50 g of magnesium stearate is weighed and introduced intothe mixing machine and mixed for 1 minute.

    ______________________________________                                        (1-2) Mixture formulation (10 kg)                                             ______________________________________                                        Compound 1                 7900 g                                             crystalline cellulose (trade name: Abicel PH-301                                                         2000 g                                             (average particle diameter: 40 microns))                                      magnesium stearate         50 g                                               light silicic anhydride (apparent specific gravity (bulk                                                 50 g                                               density) 50 g/l)                                                              ______________________________________                                    

(2) Tabletting Step, Coating Step

The tabletting step and coating step were carried out in the same manneras in Example 1.

EXAMPLE 3

(1) Mixing Step

The following mixing apparatus was used for mixing each ingredient.

Mixing apparatus: POWREX V-type mixing machine FMV100

(1-1) Mixing method

1000 g of crystalline cellulose, 550 g of milk sugar, and 50 g of lightsilicic anhydride shown in the mixture formulation below are weighted,introduced into the mixing machine and mixed for 5 minutes.

The total amount of Compound 1 is divided into 4 portions and eachportion is added to said mixture at 5-minute intervals and mixed in it.

Thereafter, 50 g of magnesium stearate is weighed and introduced intothe mixing machine and mixed for 1 minute.

    ______________________________________                                        (1-2) Mixture formulation (10 kg)                                             ______________________________________                                        Compound 1                 8350 g                                             crystalline cellulose (trade name: Abicel PH-F20                                                         1000 g                                             (average particle diameter: 17 microns))                                      milk sugar                 550 g                                              magnesium stearate         50 g                                               light silicic anhydride (apparent specific gravity (bulk                                                 50 g                                               density) 50 g/l                                                               ______________________________________                                    

(2) Tabletting Step, Coating Step

The tabletting step and coating step were carried out in the same manneras in Example 1.

EXAMPLE 4

(1) Mixing Step, Tabletting Step

The mixing step and tabletting step were carried out in the same manneras in Example 1.

(2) Coating Step

(2-1) Coating method

The coating method is carried out in the same manner as in Example 1until the step of drying, and 5 g of carnauba wax is further added, andthe number of revolutions is set at 5 rpm and the machine is operatedfor 5 minutes.

    ______________________________________                                        (2-2) Formulation of the coating liquid                                       Hydroxypropyl methyl cellulose 2910                                                                 400 g                                                   Macrogol 6000         120 g                                                   Titanium oxide        28 g                                                    Ion-exchanged water   4000 g                                                  (2-3) Lubricant                                                               Powder carnauba wax   5 g                                                     ______________________________________                                    

COMPARATIVE EXAMPLE 1

(1) Mixing Step

The following mixing apparatus was used for mixing each ingredient.

Mixing apparatus: POWREX V-type mixing machine FMV100

(1-1) Mixing method

1000 g of crystalline cellulose and 50 g of light silicic anhydrideshown in the mixture formulation below are weighted, introduced into themixing machine and mixed for 5 minutes.

The total amount of Compound 1 is divided into 4 portions and eachportion is added to said mixture at 5-minute intervals and mixed in it.

Thereafter, 50 g of magnesium stearate is weighed and introduced intothe mixing machine and mixed for 1 minute.

Because it was difficult to mix Compound 1 with water, 890 g water wasadded by spraying.

    ______________________________________                                        (1-2) Mixture formulation (10 kg)                                             ______________________________________                                        Compound 1               8010 g                                               water                    890 g                                                crystalline cellulose (trade name: Abicel PH-F20                                                       1000 g                                               (average particle diameter: 17 microns)                                       magnesium stearate       50 g                                                 light silicic anhydride (apparent specific gravity                                                     50 g                                                 (bulk density) 30 g/l)                                                        ______________________________________                                    

COMPARATIVE EXAMPLE 2

(1) Mixing Step

The following mixing apparatus was used for mixing each ingredient.

Mixing apparatus: POWREX v-type mixing machine FMV100

(1-1) Mixing method

1000 g of crystalline cellulose and 50 g of light silicic anhydrideshown in the mixture formulation below are weighted, introduced into themixing machine and mixed for 5 minutes.

The total amount of Compound 1 is divided into 4 portions and eachportion is added to said mixture at 5-minute intervals and mixed in it.

Thereafter, 50 g of magnesium stearate is weighed and introduced intothe mixing machine and mixed for 1 minute.

    ______________________________________                                        (1-2) Mixture formulation (10 kg)                                             ______________________________________                                        Compound 1                 8900 g                                             crystalline cellulose (trade name: Abicel PH-301                                                         1000 g                                             (average particle diameter: 40 microns)                                       magnesium stearate         50 g                                               light silicic anhydride (apparent specific gravity (bulk                                                 50 g                                               density) 30 g/l)                                                              ______________________________________                                    

(2) Tabletting Step, Coating Step

The tabletting step and coating step were carried out in the same manneras in Example 1.

COMPARATIVE EXAMPLE 3

(1) Mixing Step

The following mixing apparatus was used for mixing each ingredient.

Mixing apparatus: POWREX V-type mixing machine FMV100

(1-1) Mixing method

1000 g of crystalline cellulose and 50 g of light silicic anhydrideshown in the mixing formulation below are weighted, introduced into themixing machine and mixed for 5 minutes.

The total amount of Compound 1 is divided into 4 portions and eachportion is added to said mixture at 5-minute intervals and mixed in it.

Thereafter, 50 g of magnesium stearate is weighed and introduced intothe mixing machine and mixed for 1 minute.

    ______________________________________                                        (1-2) Mixture formulation (10 kg)                                             ______________________________________                                        Compound 1                 8900 g                                             crystalline cellulose (trade name: Abicel PH-302                                                         1000 g                                             (average particle diameter: 120 microns)                                      magnesium stearate         50 g                                               light silicic anhydride (apparent specific gravity (bulk                                                 50 g                                               density) 30 g/l)                                                              ______________________________________                                    

(2) Tabletting Step, Coating Step

The tabletting step and coating step were carried out in the same manneras in Example 1.

COMPARATIVE EXAMPLE 4

(1) Mixing Step

The following mixing apparatus was used for mixing each ingredient.

Mixing apparatus: POWREX V-type mixing machine FMV100

(1-1) Mixing method

50 g of light silicilic anhydride in the mixture formulation below isweighed and introduced into the mixing machine.

The total amount of Compound 1 is divided into 4 portions and eachportion is added to it at 5-minute intervals and mixed in it.

Thereafter, 50 g of magnesium stearate is weighed and introduced intothe mixing machine and mixed for 1 minute.

    ______________________________________                                        (1-2) Mixture formulation (10 kg)                                             ______________________________________                                        Compound 1                 9900 g                                             magnesium stearate         50 g                                               light silicic anhydride (apparent specific gravity (bulk                                                 50 g                                               density) 30 g/l)                                                              ______________________________________                                    

(2) Tabletting Step, Coating Step

The tabletting step and coating step were carried out in the same manneras in Example 1.

COMPARATIVE EXAMPLE 5

(1) Mixing Step

The following mixing apparatus was used for mixing each ingredient.

Mixing apparatus: POWREX V-type mixing machine FMV100

(1-1) Mixing method

1000 g of crystalline cellulose in the mixture formulation below isweighted and introduced into the mixing machine.

The total amount of Compound 1 is divided into 4 portions and eachportion is added to said mixture at 5-minute intervals and mixed in it.

Thereafter, 50 g of magnesium stearate is weighed and introduced intothe mixing machine and mixed for 1 minute.

    ______________________________________                                        (1-2) Mixture formulation (10 kg)                                             ______________________________________                                        Compound 1               8950 g                                               crystalline cellulose (trade name: Abicel PH-F20                                                       1000 g                                               (average particle diameter: 17 microns)                                       magnesium stearate       50 g                                                 ______________________________________                                    

(2) Tabletting Step, Coating Step

The tabletting step and coating step were carried out in the same manneras in Example 1.

COMPARATIVE EXAMPLE 6

(1) Mixing Step

The following mixing apparatus was used for mixing each ingredient.

Mixing apparatus: POWREX V-type mixing machine FMV100

(1-1) Mixing method

9950 g of Compound 1 and 50 g of magnesium stearate shown in the mixtureformulation below are weighted, introduced into the mixing machine andmixed for 1 minute.

    ______________________________________                                        (1-2) Mixture formulation (10 kg)                                             ______________________________________                                        Compound 1       9950 g                                                       magnesium stearate                                                                             50 g                                                         ______________________________________                                    

(2) Tabletting Step, Coating Step

The tabletting step and coating step were carried out in the same manneras in Example 1.

COMPARATIVE EXAMPLE 7

Tablets prepared in only the tabletting step in Example 1 without thecoating step.

TEST EXAMPLE 1

In tablets obtained under a tabletting pressure of 2 tons or less,powder fluidity due to scattering of the weights of base tablets wasindicated in the frequency of occurrence of fracture and cracking incoating. The present article showed compressibility in this appearancetest because it is highly hygroscopic to increase its weight during awearing test.

The test results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                                             Tablet-                                                                       ting                                           Scattering in weights          prop-                                          of base tablets                                                                             Fracture & cracking                                                                            erties                                   ______________________________________                                        Ex-   Small         None             ⊚                         ample 1                                                                       Ex-   Small         None             ⊚                         ample 2                                                                       Ex-   Small         None             ⊚                         ample 3                                                                       Com.  unable to tablet                                                                            --               --                                       Ex. 1                                                                         Com.  Small         cracks on surface                                                                              Δ                                  Ex. 2                                                                         Com.  Small         cracks on surface, fracture at                                                                 Δ                                  Ex. 3               edge                                                      Com.  Small         cracks on surface, fracture at                                                                 Δ                                  Ex. 4               edge                                                      Com.  Middle        None             ◯                            Ex. 5                                                                         Com.  Large         cracks on surface, fracture at                                                                 X                                        Ex. 6               edge                                                      ______________________________________                                    

Comparative Example 1 to which water was added could not be sufficientlymixed because of its deliquescence and stringing caused by water, andeven its tabletting was unable.

In the preparations without using water, tabletting and coating wereable in any examples and comparative examples, and tablets free ofproblems with powder fluidity and compressibility were obtained inExamples 1, 2 and 3.

A formulation to which crystalline cellulose is not added is shown inComparative Example 4, a formulation to which light silicic anhydride isnot added is shown in Comparative Example 5, and a formulation to whichboth of them are not added is shown in Comparative Example 6. Ifcrystalline cellulose is not added, tabletting properties(compressibility) are significantly deteriorated, and cracks appear onthe surfaces of tablets. In the formulation to which light silicicanhydride is not added, powder fluidity is lowered and scattering in theweights of tablets is very high. When both of them are not added,scattering in the weights of tablets is extremely high, while there aremany cracks and fracture, and tabletting properties are poor.

In addition, a formulation to which crystalline cellulose with anaverage particle diameter of 40 microns is added is shown in ComparativeExample 2, and a formulation to which crystalline cellulose with anaverage particle diameter of 120 microns is added is shown inComparative Example 3, and both of them were examples where lightsilicic anhydride with an apparent specific gravity (bulk density) 30g/l was used. These comparative examples show that even if the averageparticle diameter of crystalline cellulose added is larger, tablettingis made feasible by adding light silicic anhydride with low apparentspecific gravity (bulk density) (Example 2), but if light silicicanhydride with large apparent specific gravity (bulk density) is added,cracking and fracture frequently occur while tabletting properties aremade poor.

Further, tablets with a high drug content can be produced by use oflight silicic anhydride with low apparent density (bulk density) andcrystalline cellulose with low average particle diameter as shown inExample 1, thus contributing to a reduction in the dosage of thepharmaceutical preparation. The formulation of the tablets according tothe present invention enables stable and direct tabletting using onlythe mixing step without any granulation step, to sufficiently cope withsuccessive production.

TEST EXAMPLE 1

The present tablets are deformed when the water content exceeds 7%, andthey deliquesce upon further absorption of water The increase instability by coating was compared in terms of deformation after storageat 60° C. under a relative humidity of 90% for 20 minutes. Theastringency of the tablets when placed for 30 seconds in the mouth wasalso compared.

The results of the test are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                       Deformation  Astringency                                       ______________________________________                                        Example 1      absent       absent                                            Example 4      absent       absent                                            Com. Ex. 7     present      present                                           ______________________________________                                    

It is understood that by coating, the stability of tablets is increasedand their stringency is masked, so easily administered tablets areobtained.

INDUSTRIAL APPLICABILITY

As described above, the pharmaceutical composition and tablets of thepresent invention have the great advantages that they are superior indosage and administration methods to peroral cholesterol depressantscontaining conventional anion exchange resin, and further that even atthe time of manufacturing, no granulation step is required. Further, bycoating the resulting tablets with cellulose, it is possible to obtaintablets easily administered without any stringency of the drug.

We claim:
 1. A pharmaceutical composition comprising a tablet obtainableby admixing in the absence of water, silicon dioxide, crystallinecellulose, a pharmaceutically acceptable carrier, and a non-crosslinkedanion exchange resin represented by the formula (I): ##STR6## wherein R₁is an aralkyl group having from 7 to 10 carbon atoms or an alkyl grouphaving from 1-20 carbon atoms; R₂ and R₃ are each independently the sameor different and represent a lower alkyl group having from 1-4 carbonatoms; R₄ is a hydrogen or a lower alkyl group having from 1-4 carbonatoms; X is a physiologically acceptable counter ion; n is an integer offrom 1 to 3; and p is an average degree of polymerization of from 10 to10,000, wherein said silicon dioxide is present in an amount of 0.01 to5% by weight relative to the total weight of base tablet and whereinsaid crystalline cellulose is present in the amount of 0.1 to 30% byweight relative to the total weight of the base tablet.
 2. Thepharmaceutical composition of claim 1 wherein the anion exchange resinis poly(acryloxyethyl-N,N-dimethyl-N'benzylammonium chloride).
 3. Thepharmaceutical composition of claim 1 wherein the silicon dioxide ispresent in an amount of 0.1 to 5% by weight of the tablet.
 4. Thepharmaceutical composition of claim 1 wherein the crystalline celluloseis present in an amount of about 1 to 30% by weight of the tablet. 5.The pharmaceutical composition of claim 1 wherein the apparent specificgravity of the silicon dioxide is 70 g/l to 20 g/l, and the averageparticle diameter of crystalline cellulose is 50 to 10 microns.
 6. Thepharmaceutical composition of claim 1 wherein the tablet is coated withan agent containing cellulose.
 7. The pharmaceutical composition ofclaim 6 wherein the cellulose is hydroxypropyl methyl cellulose.
 8. Apharmaceutical tablet obtained by admixing in the absence of water,silicon dioxide, crystalline cellulose, a pharmaceutically acceptablecarrier, and a non-crosslinked anion exchange resin represented byformula (I): ##STR7## wherein R₁ is an aralkyl group having from 7 to 10carbon atoms or an alkyl group having from 1-20 carbon atoms; R₂ and R₃are each independently the same or different and represent a lower alkylgroup having from 1-4 carbon atoms; R₄ is a hydrogen or a lower alkylgroup having from 1-4 carbon atoms; X is a physiologically acceptablecounter ion; n is an integer of from 1 to 3; and p is an average degreeof polymerization of from 10 to 10,000, and forming a tablet from theadmixture, wherein said silicon dioxide is present in an amount of 0.01to 5% by weight relative to the total weight of base tablet and whereinsaid crystalline cellulose is present in the amount of 0.1 to 30% byweight relative to the total weight of the base tablet.
 9. Apharmaceutical tablet of claim 8 wherein the anion exchange resin ispoly(acryloxyethyl-N,N-dimethyl-N'benzylammonium chloride).
 10. Apharmaceutical tablet of claim 8 wherein the silicon dioxide is presentin an amount of 0.1 to 5% by weight of the tablet, and the crystallinecellulose is present in an amount of about 1 to 30% by weight of thetablet.
 11. A pharmaceutical tablet of claim 8 wherein the apparentspecific gravity of the silicon dioxide is 70 g/l to 20 g/l, and theaverage particle diameter of crystalline cellulose is 50 to 10 microns.12. A pharmaceutical tablet of claim 8 further comprising coating thetablet with an agent containing cellulose.
 13. A method for producing apharmaceutical composition comprising a tablet, the methodcomprising:(a) admixing in the absence of water, silicon dioxide,crystalline cellulose, a pharmaceutically acceptable carrier, and anon-crosslinked anion exchange resin represented by formula (I):##STR8## wherein R₁ is an aralkyl group having from 7 to 10 carbon atomsor an alkyl group having from 1-20 carbon atoms; R₂ and R₃ are eachindependently the same or different and represent a lower alkyl grouphaving from 1-4 carbon atoms; R₄ is a hydrogen or a lower alkyl grouphaving from 1-4 carbon atoms; X is a physiologically acceptable counterion; n is an integer of from 1 to 3; and p is an average degree ofpolymerization of from 10 to 10,000, and (b) forming a tablet from theadmixture, wherein said silicon dioxide is present in an amount of 0.01to 5% by weight relative to the total weight of base tablet and whereinsaid crystalline cellulose is present in the amount of 0.1 to 30% byweight relative to the total weight of the base tablet.
 14. The methodof claim 13 wherein the anion exchange resin ispoly(acryloxyethyl-N,N-dimethyl-N'benzylammonium chloride).
 15. Themethod of claim 13 wherein the silicon dioxide is present in an amountof 0.1 to 5% by weight of formed the tablet, and the crystallinecellulose is present in an amount of about 1 to 30% by weight of theformed tablet.
 16. The method of claim 13 wherein the apparent specificgravity of the silicon dioxide is 70 g/l to 20 g/l, and the averageparticle diameter of crystalline cellulose is 50 to 10 microns.
 17. Themethod of claim 13 further comprising coating the tablet with an agentcontaining cellulose.